U. S. Department of health & human services




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Pharmacopeia, and is widely used. Although CBER and

the Office of Vaccines has always accepted materials

that meet the requirements of the USP definition, we

are not bound to follow that definition.

Thimerosal is the most widely used

preservative in vaccines, and has been in use since

the 1930s. It was first introduced into this

diphtheria toxoid by Eli Lilly. It is currently

present in about 50 U.S. licensed biological products

in concentrations ranging from 0.003 to 0.01 percent.

Thimerosal use was reviewed internally within then the

Bureau of Biologics in 1976, and it was concluded that

there were no harmful effects of Thimerosal at the

doses that were received during a lifetime.

Id also note that Thimerosal, which is a

mercuric derivative with ethyl and thiosalicylate 

attached to it, and it breaks down the ethyl mercury

and thiosalicylate.

The Food and Drug Modernization Act of

1997 mandated that FDA compile a list of mercury 

containing products and subsequently conduct an

analysis of the effect of mercury on recipients of

these Thimerosal containing or mercury containing

products. The product listing is due to Congress in

November of this year. There is no stated deadline

for the analysis of the effects.

Now, independent of the FDA Modernization

Act, there has been a concern in various corners,

including CBER, of the increase in accumulated amount

of mercury that children are receiving through

vaccines. At FDA, we have been discussing this issue

with manufacturers and have requested them that as new

products are developed that they not contain

Thimerosal unless absolutely necessary.

A number of U.S. licensed vaccines contain

Thimerosal, and these are presented on the next two

slides. These vaccines include DTaP, all the DT&Td

products and hepatitis B and a variety of additional

vaccines, including influenza, meningococcal

polysaccharide vaccines, and rabies vaccines.

There are, however, a number of vaccines

that are Thimerosal free, either by virtue of

presentation in single dose images, or through the use

of alternative preservatives. These vaccines include

some DTaP, for example, Infarix, HIB vaccines, HIB

hepatitis B combinations, Comvax, IPV/OPV, MMR, et

cetera.

However, we are still left with several

vaccines for which there is no Thimerosal free

presentation, and these include the whole cell

containing pertussis vaccines and the toxoid vaccines,

the diphtheria and tetanus toxoid vaccines.

One can calculate the maximum exposure to

Thimerosal that a child might receive by age six

months or by age two years. Excluding the pediatric

use of influenza vaccine, the total, the maximum

amount received is 187½ micrograms by six months, and

237 micrograms by two years of age.

Through the use of particular vaccines,

however, this exposure could be reduced to zero, as is

presented on the next slide and is in your handouts,

by judicious choice of schedule and vaccines, with the

exception of, perhaps, influenza if thats needed, one

could have a completely Thimerosal free schedule.

Now, the question remains as to the level

of risk, that even the maximum exposure to Thimerosal

containing vaccines might pose. At the outside in a

state that there is no data to think that this

exposure to Thimerosal presents any risk, nonetheless,

when we present the current U.S. guidelines for

exposure, and I use the plural because there are more

than one, the EPA guidelines approximately 0.1

microgram per kilogram per day, the ATSDR 0.3

micrograms, the FDA guideline 0.4. Theres also a WHO

guideline, which is 0.47 for adults and 0.1 micrograms

per day. These are given as weeks, so just divide by

seven.

Now, using these numbers, the suggested

limits on methyl mercury intake, for the first six

months for different birth cohorts in infants can be

calculated, this is on the next slide, and one can see

that for all birth cohorts, weight cohorts, the

vaccination schedule would exceed the WHO guidelines

and EPA guidelines, barely exceeds the ATSDR guideline

at the lowest five percent birth weight, and does not

exceed the FDA guideline. And, by two years of age

its not exceeding any one of these guidelines.

Now, there are many caveats to using these

recommendations, and this includes, you know, is

methyl mercury as toxic as ethyl mercury, routes of

administration, dose schedule, magnitude of doses,

pharmacokinetics, the rate of elimination and so on.

Let me now discuss whats been happening

over the past several months, keeping these background

data in mind. The most significant event was the

AAP/PHS joint statement that was issued on July 7, and

these groups agree that, Thimerosal containing

vaccines should be removed as soon as possible. The

groups also recommended that, Clinicians and parents

can take advantage of the flexibility within the

existing schedule to postpone the first dose of

hepatitis B from birth until two to six months.

There was no change in the recommendation to immunize

infants for hepatitis B surface antigen positive

mothers.

The joint statement also called for a

formal request from FDA to the manufacturers for a

plan to reduce or eliminate Thimerosal from their

vaccines, a review of pertinent data in a public

workshop, expedited FDA review of manufacturing

supplements for removal of Thimerosal, additional

studies to understand the risks of Thimerosal,

monitoring changes in immunization practices, and to

provide better information to health care workers to

enable them to better communicate with parents and

consumer groups.

Many of these recommendations have already

been implemented. FDA issued its letter to the

manufacturers on July 1, actually a week in advance of

this statement, and the letter asked manufacturers to

provide plans for removing Thimerosal, if they intend

to remove Thimerosal, or if they plan on keeping

Thimerosal an explanation for this decision.

Manufacturers have responded to the FDA

letter. Additionally, through PhRMA, the vaccine

industry supports the goal of Thimerosal free

vaccines and is working closely with FDA and other

government agencies, as well as the American Academy

of Pediatrics, to meet this objective. A public

workshop was held on August 11th and 12th at the NIH,

and data related to Thimerosal use and safety were

reviewed. And finally, Merck submitted a supplement

for Thimerosal free hepatitis B vaccine and this was

approved on August 22nd. It was reviewed

expeditiously.

The final issue is where are we going, and

I think that Thimerosal will be removed from most, if

not all, vaccines, and the alternative of choice, at

least in the United States, will probably be single

dose presentations. Alternative preservatives will

also be used, but we need to consider increased

toxicity testing for these, so that we dont get in

the similar position that we were with Thimerosal,

and, perhaps, we might  we should allow, or might

allow, a decreased effectiveness relative to the

current USP requirements for vaccines as

preservatives, which are rather stringent

requirements.

Thank you.

CHAIR GREENBERG: Thank you, Bill.

Can we have some lights?

Well, we are doing very well here.

This is, obviously, panel members, an

important and high public visibility issue. Bill has

presented this very brief review to keep us appraised

of whats going on, but I think we have a time for a

few questions if any of you have them.

Dixie?

DOCTOR SNIDER: Well, I just want to add to

what Bill has said, bringing us up to date, he

mentioned that the AAP/PHS statement talked about

postponing the hep B dose, and on Friday the MMWR,

taking the approval that Merck proceed for their

hepatitis B vaccine, CDC issued some new

recommendations to use the Thimerosal preservative

free vaccines to vaccinate infants at birth. The

reason for that, some of which was given in the MMWR

article, is that theres a lot of confusion, and many

hospitals had discontinued hep B vaccines at birth

altogether, even for infants of high risk mothers,

including those that were known to be hepatitis B

positive. So, we felt it important to restart the

infant hep B immunization with the Thimerosal free

product.

People can read the article for further

details.

DOCTOR EGAN: Yes, thank you very much for

adding that point, which slipped my presentation.

CHAIR GREENBERG: Thank you, Dixie.

Actually, thats heartening, because that

was a problem, and, clearly, no matter how clear you

try to be the public and physicians were confused by

this issue, and evidently some high risk children were

not vaccinated when they should have been.

Any other 

DOCTOR FAGGETT: Harry, Walter Faggett,

Chairman  Section NMA.

One question about the Merck vaccines,

what kind of inventory do they have, how available is

it going to be for immunizing those children in the

nursery?

DOCTOR EGAN: Yes. I cant comment on the

current inventory of Thimerosal free vaccine in Merck,
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